Publications by authors named "Javier Padillo"

23 Publications

  • Page 1 of 1

Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells.

Cell Physiol Biochem 2020 05;54(3):457-473

Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain,

Background/aims: Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells.

Methods: The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern.

Results: The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced P-Cdk4/Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR-720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells.

Conclusion: The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cells.
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http://dx.doi.org/10.33594/000000230DOI Listing
May 2020

Response to Comment on "Does the Artery-first Approach Improve the Rate of R0 Resection in Pancreatoduodenectomy? A Multicenter, Randomized, Controlled Trial".

Ann Surg 2020 Jan 6. Epub 2020 Jan 6.

Department of Surgery, Hospital Clínico, University of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain Department of Surgery, Hospital Virgen del Rocío, Sevilla, Spain On behalf of all authors.

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http://dx.doi.org/10.1097/SLA.0000000000003773DOI Listing
January 2020

Influence of robotics in surgical complication rate in elderly population with rectal cancer.

Aging Clin Exp Res 2020 Aug 10;32(8):1585-1589. Epub 2019 Sep 10.

Department of General and Digestive Surgery, Colorectal Surgery Unit, "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville, Seville, 41013, Spain.

Background: Rectal cancer surgery is a technically complex procedure. Moreover, short-term outcomes show high rate of complications especially in elderly and laparoscopic surgery has not demonstrated to be able to reduce this complication rate. Robotics has several advantages in pelvic surgical procedures, which could have an impact in complication rates in elderly patients.

Aims: The aim of our study is to demonstrate whether robotic surgery has any influence on the reduction of complications in the aged population undergoing rectal cancer.

Methods: We performed a retrospective analysis of a prospective database of 151 patients who underwent robotic surgery for rectal cancer. We divided our population into three groups: under 65-year-old, between 65- and 80-year-old and above 80-year-old. We recorded complications in each group intra and post procedure.

Results: The present study included 151 patients (94 males). Of them, 77 patients were under 66 year old, 63 patients were between 66 and 79 year old and 11 patients were 80 year old and above. The analysis showed conversion rates of 10.38%, 13.69%, 27.27%, and the complication rate of 23.4%, 23.8%, and 27.3% in each group. Univariate analysis showed no differences between the three groups. Nevertheless, there were statistical differences from BMI, ASA and neoadjuvant therapy. In multivariant analysis only neoadjuvant therapy was significant.

Conclusions: Robotic approach does not decrease complications in elderly population and conversion is similar in these age groups. So we should not rule out robotic surgery in elderly patients, although we must select each case with a multidisciplinary approach.
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http://dx.doi.org/10.1007/s40520-019-01331-2DOI Listing
August 2020

Does the Artery-first Approach Improve the Rate of R0 Resection in Pancreatoduodenectomy?: A Multicenter, Randomized, Controlled Trial.

Ann Surg 2019 11;270(5):738-746

Department of Surgery, Hospital Virgen del Rocío, Sevilla, Spain.

Objective: To compare the rates of R0 resection in pancreatoduodenectomy (PD) for pancreatic and periampullary malignant tumors by means of standard (ST-PD) versus artery-first approach (AFA-PD).

Background: Standardized histological examination of PD specimens has shown that most pancreatic resections thought to be R0 resections are R1. "Artery-first approach" is a surgical technique characterized by meticulous dissection of arterial planes and clearing of retropancreatic tissue in an attempt to achieve a higher rate of R0. To date, studies comparing AFA-PD versus ST-PD are retrospective cohort or case-control studies.

Methods: A multicenter, randomized, controlled trial was conducted in 10 University Hospitals (NCT02803814, ClinicalTrials.gov). Eligible patients were those who presented with pancreatic head adenocarcinoma and periampullary tumors (ampulloma, distal cholangiocarcinoma, duodenal adenocarcinoma). Assignment to each group (ST-PD or AFA-PD) was randomized by blocks and stratified by centers. The primary end-point was the rate of tumor-free resection margins (R0); secondary end-points were postoperative complications and mortality.

Results: One hundred seventy-nine patients were assessed for eligibility and 176 randomized. After exclusions, the final analysis included 75 ST-PD and 78 AFA-PD. R0 resection rates were 77.3% (95% CI: 68.4-87.4) with ST-PD and 67.9% (95% CI: 58.3-79.1) with AFA-PD, P=0.194. There were no significant differences in postoperative complication rates, overall 73.3% versus 67.9%, and perioperative mortality 4% versus 6.4%.

Conclusions: Despite theoretical oncological advantages associated with AFA-PD and evidence coming from low-level studies, this multicenter, randomized, controlled trial has found no difference neither in R0 resection rates nor in postoperative complications in patients undergoing ST-PD versus AFA-PD for pancreatic head adenocarcinoma and other periampullary tumors.
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http://dx.doi.org/10.1097/SLA.0000000000003535DOI Listing
November 2019

Impact of Early Initiated Everolimus on the Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Transplantation 2018 12;102(12):2056-2064

Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain.

Background: Many centers implement everolimus-based immunosuppression in liver transplant patients with hepatocellular carcinoma. We aimed to explore the potential impact of early initiated everolimus on tumor recurrence after liver transplantation.

Methods: This study included 192 patients with hepatocellular carcinoma undergoing liver transplantation among who 64 individuals were prospectively enrolled (2012-2015) and received early initiated everolimus (ie, started between postoperative day 15 to 21), whereas the remaining 128 patients acted as historical controls without everolimus. Propensity score matching was performed to ensure comparability. Multivariate Cox regression and competing risks analysis were used to control for potential confounders.

Results: Patients with and without everolimus were comparable in terms of number of nodules (P = 0.37), total tumor diameter (P = 0.44), Milan criteria fulfillment (P = 0.56), and histological differentiation (P = 0.61), but there were increased microvascular invasion rates in the everolimus group (26.5% vs 13.3%; P = 0.026). Tumor recurrence rates were similar with and without everolimus (10.9% vs 9.9% at 36 months respectively; P = 0.18). After controlling for microvascular invasion among other potential confounders, everolimus had no significant impact on tumor recurrence, neither in the multivariate Cox regression (relative risk = 3.23; P = 0.09), nor in the competing risks analysis for tumor recurrence-death (relative risk = 1.02; P = 0.94). Patients receiving everolimus had reduced tacrolimus trough concentrations and lower serum creatinine within the first 18 months postliver transplantation.

Conclusion: Everolimus may not be universally prescribed to prevent tumor recurrence in liver transplant patients with hepatocellular carcinoma. Future randomized trials should be focused on patients with histological features of increased tumor aggressiveness, in whom the potential benefit would be higher.
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http://dx.doi.org/10.1097/TP.0000000000002270DOI Listing
December 2018

Learning curve in robotic rectal cancer surgery: current state of affairs.

Int J Colorectal Dis 2016 Dec 6;31(12):1807-1815. Epub 2016 Oct 6.

Department of General and Digestive Surgery, Colorectal Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain.

Introduction: Robotic-assisted rectal cancer surgery offers multiple advantages for surgeons, and it seems to yield the same clinical outcomes as regards the short-time follow-up of patients compared to conventional laparoscopy. This surgical approach emerges as a technique aiming at overcoming the limitations posed by rectal cancer and other surgical fields of difficult access, in order to obtain better outcomes and a shorter learning curve.

Material And Methods: A systematic review of the literature of robot-assisted rectal surgery was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search was conducted in October 2015 in PubMed, MEDLINE and the Cochrane Central Register of Controlled Trials, for articles published in the last 10 years and pertaining the learning curve of robotic surgery for colorectal cancer. It consisted of the following key words: "rectal cancer/learning curve/robotic-assisted laparoscopic surgery".

Results: A total of 34 references were identified, but only 9 full texts specifically addressed the analysis of the learning curve in robot-assisted rectal cancer surgery, 7 were case series and 2 were non-randomised case-comparison series. Eight papers used the cumulative sum (CUSUM) method, and only one author divided the series into two groups to compare both. The mean number of cases for phase I of the learning curve was calculated to be 29.7 patients; phase II corresponds to a mean number 37.4 patients. The mean number of cases required for the surgeon to be classed as an expert in robotic surgery was calculated to be 39 patients.

Conclusion: Robotic advantages could have an impact on learning curve for rectal cancer and lower the number of cases that are necessary for rectal resections.
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http://dx.doi.org/10.1007/s00384-016-2660-0DOI Listing
December 2016

Analysis of conversion factors in robotic-assisted rectal cancer surgery.

Int J Colorectal Dis 2014 Jun 21;29(6):701-8. Epub 2014 Mar 21.

Department of Surgery, University Hospital Virgen del Rocío, Seville, Spain,

Background: Robotic surgical management of rectal cancer has a series of advantages which might facilitate the surgical approach to the pelvic cavity and reduce conversion rates. The aim of the present study is to identify independent factors for conversion during robotic rectal cancer surgery.

Methods: A total of 67 patients underwent preoperative CT scan in order to obtain a three-dimensional image of the pelvis, the tumour and prostate. We measured maximum and minimum ilio-iliac, sacral promontory-pubis, coccyx-pubis diameters and maximum lateral axis. Further variables under consideration were age, BMI and use of neoadjuvant therapy. We recorded short-term follow-up outcomes of the resected tumour.

Results: The present study included 67 patients (39 males) with an average age of 65.11 ± 10.30 years and a BMI of 27.70 ± 3.97 kg/m(2). Operative procedures included nine abdominoperineal resections and 58 low anterior resections. There were 15 (22.38 %) conversions. Mean operating time was 192.2 ± 42.73 min. Minimum ilio-iliac, maximum ilio-iliac, promontory-pubic and coccyx-pubis diameter as well as maximum lateral axis were 100.38 ± 7.65, 107.10 ± 10.01, 109.97 ± 9.20, 105.61 ± 9.27 and 129.01 ± 9.94 mm, respectively. Mean tumour volume was 37.06 ± 44.08 cc; mean prostate volume was 42.07 ± 17.49 cc. The univariate analysis of the variables showed a correlation between conversion and BMI and minimum ilio-iliac and coccyx-pubis diameters (p = 0.004, 0.047, 0.046). In the multivariate analysis, the only independent predictive factor for conversion was the BMI (p = 0.004).No correlation was found between conversion and sex, age, tumour volume or the rest of pelvic diameters.

Conclusion: BMI is an independent factor for conversion in robotic-assisted rectal cancer surgery.
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http://dx.doi.org/10.1007/s00384-014-1851-9DOI Listing
June 2014

The protective role of coenzyme Q10 in renal injury associated with extracorporeal shockwave lithotripsy: a randomised, placebo-controlled clinical trial.

BJU Int 2014 Jun 29;113(6):942-50. Epub 2014 Jan 29.

Department of Urology, Reina Sofia University Hospital, Cordoba, Spain.

Objective: To determine the efficacy of coenzyme Q10 (CoQ10) in preventing renal injury in patients with lithiasis undergoing extracorporeal shockwave lithotripsy (ESWL).

Patients And Methods: Prospective, randomised, double-blind, placebo-controlled clinical trial of 100 patients with renal lithiasis who were treated with ESWL. The patients were distributed randomly into two groups receiving either placebo or CoQ10 (200 mg/day), a powerful antioxidant with vasoactive properties, orally administered during the week before ESWL and for 1 week after. Renal dysfunction markers, vasoactive hormones, oxidative stress, plasma levels of several interleukins and vascular resistance index (VRI) using Doppler ultrasound were evaluated the week before ESWL, 2 h before ESWL and at 2 h, 24 h and 7 days after ESWL.

Results: There was a significant increase in glomerular filtration (P = 0.013), as well as a decrease in the albumin/creatinine ratio and the β2 -microglobulin level (P = 0.02) after 1 week of treatment in the CoQ10 group. These changes were maintained at the follow-up after ESWL. The administration of CoQ10 was associated with improvement in vasoactive hormone parameters, VRI and interleukin levels. These improvements were maintained until the end of the follow-up period. However, the administration of CoQ10 was not associated with significant changes in the oxidative stress parameters.

Conclusion: Our results indicate that CoQ10 administration improves renal function and vasoactive and inflammation parameter values, allowing for preconditioning before the tissue insult caused by ESWL.
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http://dx.doi.org/10.1111/bju.12485DOI Listing
June 2014

Learning curve for robotic-assisted laparoscopic rectal cancer surgery.

Int J Colorectal Dis 2013 Jun 15;28(6):815-21. Epub 2012 Dec 15.

Department of General Surgery, University Hospital Virgen del Rocío, C/Jándula 2, Bl-3, P-3, 4º2, 41013, Sevilla, Spain.

Introduction: One of the main uses of robotic assisted abdominal surgery is the mesorectal excision in patients with rectal cancer. The aim of the present study is to analyse the learning curve for robotic assisted laparoscopic resection of rectal cancer.

Patients And Methods: We included in our study 43 consecutive rectal cancer resections (16 females and 27 males) performed from January 2008 through December 2010. Mean age of patients was 66 ± 9.0 years. Surgical procedures included both abdomino-perineal and anterior resections. We analysed the following parameters: demographic data of the patients included in the study, intra- and postoperative data, time taking to set up the robot for operations (set-up or docking time), operative time, intra- and postoperative complications, conversion rates and pathological specimen features. The learning curve was analysed using cumulative sum (CUSUM) methodology.

Results: The procedures understudied included seven abdomino-perineal resections and 36 anterior resections. In our series of patients, mean robotic set-up time was 62.9 ± 24.6 min, and the mean operative time was 197.4 ± 44.3 min. Once we applied CUSUM methodology, we obtained two graphs for CUSUM values (operating time and success), both of them showing three well-differentiated phases: phase 1 (the initial 9-11 cases), phase 2 (the middle 12 cases) and phase 3 (the remaining 20-22 cases). Phase 1 represents initial learning; phase 2 plateau represents increased competence in the use of the robotic system, and finally, phase 3 represents the period of highest skill or mastery with a reduction in docking time (p = 0.000), but a slight increase in operative time (p = 0.007).

Conclusion: The CUSUM curve shows three phases in the learning and use of robotic assisted rectal cancer surgery which correspond to the phases of initial learning of the technique, consolidation and higher expertise or mastery. The data obtained suggest that the estimated learning curve for robotic assisted rectal cancer surgery is achieved after 21-23 cases.
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http://dx.doi.org/10.1007/s00384-012-1620-6DOI Listing
June 2013

Robotic-assisted total mesorectal excision with the aid of a single-port device.

Surg Innov 2013 Aug 7;20(4):NP3-5. Epub 2012 Feb 7.

Department of General Surgery, Virgen del Rocío UH, Seville, Spain.

Unlabelled: INTRODUCTION AND INDICATIONS: Robotic surgery has numerous advantages in rectal cancer surgery. Studies have reported the advantages associated with single-port approaches, such as eliminating the need for additional incisions, as well as the difficulties inherent in this technique. The authors present a hybrid technique that they performed using a robotic total mesorectal excision with the aid of a single port-device. Materials and methods. The authors performed the technique on 2 patients using a single-port device through an umbilical incision and 3 accessory ports for the robotic arms. There was no need to place ports for the assistant's equipment or for an assistant incision.

Results And Complications: The operation time was 177.5 minutes, and there were no intraoperative or postoperative complications. Both patients were discharged 7 days after the operation.

Conclusions: This technical variation is an additional step forward for oncological surgery with minimal damage to the abdominal wall.
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http://dx.doi.org/10.1177/1553350611434643DOI Listing
August 2013

Renal function after dopamine and fluid administration in patients with malignant obstructive jaundice. A prospective randomized study.

J Gastrointestin Liver Dis 2011 Jun;20(2):161-7

Gastroenterology Department, Puerta del Mar University Hospital, Cadiz, Spain.

Background And Aims: Acute renal failure is a relevant complication in obstructive jaundice (OJ). The extracellular water volume (ECW) depletion and myocardial dysfunction affects haemodynamic and renal disturbance in patients with OJ.

Methods: A prospective open randomised study was conducted to evaluate the effect of peridrainage saline infusion associated with dopamine administration on hormonal and renal function derangements in 102 patients with malignant OJ. Patients were randomly distributed according to whether (n=64) or not (n=38) received dopamine with saline solution before endoscopic biliary drainage. Furthermore, patients receiving dopamine were randomly distributed whether (n=31) or not (n=33) received additional dopamine administration during the postdrainage phase. Different parameters such as ECW, serum levels of aldosterone, renin, atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), endothelin-1 (ET-1), urine PGE2 and creatinine clearance (CrCl) were analyzed.

Results: Fluid administration was accompanied by an increase in the ECW (p=0.01) and an improvement in the CrCl (p=0.01). Dopamine increased CrCl by 11% (p=0.04) and reduced urinary PGE2 concentration (p=0.02). After drainage, a transient worsening of CrCl was seen in patients on i.v. fluid infusion alone but not in dopamine groups (p=0.001). Improvement of CrCl after dopamine administration was found in patients with serum bilirubin > 16 mg/dl and sodium urine excretion <145 mEq/l.

Conclusions: The administration of dopamine associated with appropriate i.v. fluid infusion in the peridrainage period has an impact on renal function only in selected patients with malignant biliary obstruction. This effect is more relevant in patients with higher marked cholestasis.
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June 2011

[Prospective randomised study: robotic-assisted versus conventional laparoscopic surgery in colorectal cancer resection].

Cir Esp 2011 Aug-Sep;89(7):432-8. Epub 2011 Apr 29.

Servicio de Cirugía, Hospital Universitario Virgen del Rocío, Sevilla, España.

Introduction: Robotic-assisted surgery is playing an increasingly important role in the last few years in the treatment of colorectal oncological disease. However, there are still no studies that objectively demonstrate the advantages of this type of surgery. We present a prospective randomised study in order to compare the short-term results between colorectal robotic surgery and laparoscopic surgery.

Material And Method: A total of 56 patients diagnosed with colorectal cancer between January 2008 and January 2009, were randomised and assigned to the robotic or laparoscopic group. Age, body mass index, tumour location, conversions in each group, complications during and after surgery, and histological characteristics of the specimens obtained, were all compared.

Results: There were no significant differences between age (P=.055), body mass index (P=.12), or tumour location (P=.91). Only one patient in the robotic group required a transfusion and none in the laparoscopic group. The percentage of conversions was the same in both groups, however, the preparation times and operating times were significantly longer in patients intervened using the robotic device (P=.0001 and P=.017, respectively). There were no differences as regards the rate of complications or in the percentage of re-interventions (14.2% and 7.1%). The mean hospital stay of the patients was 9.3 (8.1) days in the robotic group and 9.2 (6.8) days in the laparoscopic (P=.79). The distal resection margin was greater in the specimen obtained using robotic surgery (P =.003) as well as the number of lymph nodes obtained in the specimen (P =.23).

Conclusion: Robotic colorectal was performed safely and effectively, and with similar clinical results. International Trial Number for this study is: ISRCTN60866560.
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http://dx.doi.org/10.1016/j.ciresp.2011.01.017DOI Listing
January 2012

Cytoprotective properties of rifampicin are related to the regulation of detoxification system and bile acid transporter expression during hepatocellular injury induced by hydrophobic bile acids.

J Hepatobiliary Pancreat Sci 2011 Sep;18(5):740-50

Liver Research Unit, Hospital Universitario Reina Sofía, IMIBIC (Instituto Maimónides para la Investigación Biomédica de Córdoba), Av. Menéndez Pidal s/n, 14004 Córdoba, Spain.

Background/purpose: Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis.

Methods: Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined.

Results: The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression.

Conclusions: The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.
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http://dx.doi.org/10.1007/s00534-011-0396-3DOI Listing
September 2011

Improvement of capecitabine antitumoral activity by melatonin in pancreatic cancer.

Pancreas 2011 Apr;40(3):410-4

Department of Surgery, Reina Sofia University Hospital, Córdoba, Spain.

Objective: The purpose of our study was to evaluate the effects of the addition of melatonin and capecitabine on experimental pancreatic cancer.

Methods: Fifty Syrian hamsters were randomized in 5 groups: group 1: no tumor induction (control group); group 2: tumor induction with BOP [N-nitrosobis(2-oxopropyl) amine]; group 3: tumor induction with BOP and melatonin administration; group 4: tumor induction with BOP and capecitabine administration; and group 5: tumor induction with BOP and administration of combined capecitabine and melatonin therapy. The evaluation of pathological tumor evolution and oxidative stress markers in pancreatic tissue was carried out.

Results: All animals under BOP exposure presented poorly or moderately differentiated pancreatic adenocarcinoma associated with increased lipoperoxide levels and decreased antioxidant activity in pancreatic tissue. Pancreatic cancer was shown in only 66% of the capecitabine-treated group and 33% of melatonin-treated group (P < 0.05), most of them moderately differentiated adenocarcinoma. When capecitabine and melatonin were combined, a well-differentiated pancreatic adenocarcinoma was observed in 10% of animals. The beneficial effect was associated with a decrease in lipoperoxide levels and increased antioxidant activity in pancreatic tissue.

Conclusions: The combined administration of capecitabine and melatonin provided an improvement in antioxidant status as well as a synergistic antitumoral effect in experimental pancreatic cancer.
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http://dx.doi.org/10.1097/MPA.0b013e318201ca4fDOI Listing
April 2011

BNP as marker of heart dysfunction in patients with liver cirrhosis.

Eur J Gastroenterol Hepatol 2010 Nov;22(11):1331-6

Department of Surgery, Virgen del Rocío University Hospital-IBiS, Sevilla, Spain.

Backgrounds: Patients with liver cirrhosis suffer various degrees of cardiac dysfunction which may be crucial in determining the outcome of surgery. The aim of this study was to determine the role of natriuretic peptides on the assessment of cardiac dysfunction in patients with liver cirrhosis.

Methods: Prospective longitudinal study of 30 patients with hepatic cirrhosis. Severity of disease was assessed according to the Child-Turcotte-Pugh and Model for End Stage Liver Disease (MELD) scores. Cardiac function was assessed using endocrine markers [atrial natriuretic peptide-brain natriuretic peptide (BNP)] and isotopic ventriculography at baseline and after stimulation with dobutamine.

Results: The ejection fraction was higher in patients with Child A+B and MELD less than 18 than in patients with advanced liver disease. A significant correlation between BNP plasma levels and MELD values was observed. Dobutamine induced a marked improvement in myocardial performance associated to a decrease in BNP levels. Multivariate analysis showed that BNP has prognostic value as a marker of cardiac ejection fraction. Patients whose baseline BNP concentrations were more than 70 pg/ml had an ejection fraction of around 45%.

Conclusion: This study has shown that increased baseline BNP concentrations may be regarded together with high Child and MELD scores, as the critical cardiac dysfunction threshold in cirrhotic patients.
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http://dx.doi.org/10.1097/MEG.0b013e32833e6b2aDOI Listing
November 2010

Simultaneous pancreas-kidney transplant: a single-center long-term outcome.

J Nephrol 2007 Mar-Apr;20(2):173-6

Department of Nephrology, University Hospital Reina Sofia, Cordoba, Spain.

Background: In patients with type 1 diabetes mellitus and end-stage renal disease, simultaneous pancreas-kidney transplantation is associated with increased survival when compared with solitary deceased kidney transplant or dialysis. We consider that the analysis of our long-term program (based in a single center) of simultaneous pancreas-kidney transplantation would provide valuable information for this therapeutic approach regarding patient and organ survival.

Methods: The outcome of 57 consecutive pancreas-kidney transplants patients was analyzed. The analysis included characteristics of the donor and recipient and survival rates of patients and both grafts. We also analyzed age and modality of renal replacement treatment as possible mortality risk factors.

Results: Ten-year patient, kidney and pancreas graft survival rates were 75.8%, 57.2% and 42.7%, respectively. Censoring for patient death, the results for 10-year kidney and pancreas survival were 78.5% and 58%, respectively.

Conclusion: Our results add evidence to support the notion that the double and simultaneous pancreas-kidney transplantation is in fact the treatment of choice in selected patients with end-stage renal failure due to type 1 diabetes mellitus.
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July 2007

Assignment of steatotic livers by the Mayo model for end-stage liver disease.

Transpl Int 2005 May;18(5):577-83

Unit of Liver Transplantation, Department of Surgery, Hospital Reina Sofía, Córdoba, Spain.

Prognosis after liver transplantation depends on a combination of recipient and donor variables. The purpose of this study is to define an allocation system of steatotic donor livers relative to recipient model for end-stage liver disease (MELD) score. We reviewed 500 consecutive OLT, computing the MELD score for each recipient. Fatty infiltration in grafts was categorized in no steatosis, 10-30%, 30-60% and > or = 60% steatosis. MELD score did not affect preservation injury and graft dysfunction, which were increased with fat content. Recipient and graft survivals lowered when increasing MELD score. Outcome in low-risk recipients (MELD < or = 9) was not altered with steatosis, except those with > or = 60%. Survival functions in moderate-risk recipients (MELD 10-19) were moderately affected with 10-30% steatosis and severely with those with >30. Exactly 30-60% steatotic grafts work poorly in high-risk recipients (MELD > or = 20), and very poorly with > or = 60% steatosis. Prognosis of candidates is optimally influenced when divergence of recipient-donor risks is presented.
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http://dx.doi.org/10.1111/j.1432-2277.2005.00091.xDOI Listing
May 2005

Immunomodulatory activity of TNF-alpha during acute liver injury induced by D-galactosamine and its protection by PGE1 in rats.

Int Immunopharmacol 2003 Feb;3(2):197-207

Unidad de Investigación, Unidad Clínica Aparato Digestivo, Hospital Universitario Reina Sofía, Av Menéndez Pidal s/n, Córdoba E-14004, Spain.

Tumour necrosis factor-alpha (TNF-alpha) mediates hepatocyte cell death by D-galactosamine (D-GalN) and its protection by prostaglandin E(1) (PGE(1)). The activation of immune system plays an important role in the development of liver injury. TNF-alpha and PGE(1) regulate the activity and cytokine release of different inflammatory cells. The present study was undertaken to determine if the noxious or hepatic protective properties of TNF-alpha during D-GalN-induced liver injury was related to an alteration by PGE(1) of the immunoregulatory activity of TNF-alpha. The role of TNF-alpha was assessed by anti-TNF-alpha antibodies to D-GalN-treated rats in the presence or absence of PGE(1). D-GalN enhanced the percentage of monocytes and T lymphocytes in the total peripheral blood mononuclear cells (PBMCs). D-GalN enhanced the activation degree of monocytes, but reduced that of T lymphocytes. D-GalN also enhanced TNF-alpha, IL-1alpha, IL-6 and IFN-gamma concentrations in blood. Anti-TNF-alpha antibodies abolished all immunological changes and greatly reduced liver damage induced by D-GalN. The protection by PGE(1) against D-GalN liver injury was associated with an increase in TNF-alpha concentration and a reduction of IL-1alpha and IL-6. These changes were associated with a reduction of monocyte activation degree and a recovery of that of T lymphocytes. Although anti-TNF-alpha antibodies abolished the protection by PGE(1) against D-GalN-liver injury, they did not essentially counteract the effect of the prostanoid in all immunological parameters studied. The present study showed that the protection against D-GalN liver damage by PGE(1) or anti-TNF-alpha was associated with similar effects on the inflammatory parameters studied. Nevertheless, the abolishment of liver protection by PGE(1) with anti-TNF-alpha in D-GalN-treated rats in the presence of a protective cytokine profile suggests that the release of TNF-alpha induced by PGE(1) pre-administration was exerting a direct protective effect on hepatocytes against D-GalN injury. Consequently, the effect of PGE(1) on inflammatory parameters studied during liver injury was unrelated to TNF-alpha.
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http://dx.doi.org/10.1016/s1567-5769(02)00259-xDOI Listing
February 2003

Tumour necrosis factor-alpha and nitric oxide mediate apoptosis by D-galactosamine in a primary culture of rat hepatocytes: exacerbation of cell death by cocultured Kupffer cells.

Can J Gastroenterol 2002 Nov;16(11):791-9

Unidad Cernica Aparto Digestivo, Hospital Universitario Reina Sofía, Córdoba, Spain.

Background: Prostaglandin E1 (PGE1) reduces cell death in experimental and clinical liver dysfunction.

Objectives: Whether PGE1 protects against D-galactosamine (D-GalN)-associated hepatocyte cell death by the regulation of tumour necrosis factor-alpha (TNF-alpha) and/or nitric oxide (NO) in hepatocytes or cocultured Kupffer cells was examined.

Methods: Anti-TNF-alpha antibodies were used to evaluate the role of TNF-alpha during D-GalN cytotoxicity and its protection by PGE1 in cocultured hepatocytes and Kupffer cells. Cell apoptosis and necrosis were assessed by DNA fragmentation and lactate dehydrogenase release, respectively. Nitrite+nitrate (NOx), as NO end products, and TNF-alpha concentrations were measured in the culture medium. The role of NO was determined by measuring inducible NO synthase (iNOS) expression and the effect of its inhibition during d-GalN cytotoxicity and its protection by PGE1.

Results: D-GalN enhanced hepatocyte cell death associated with high TNF-alpha and NOx levels in a culture medium. Anti-TNF-alpha and iNOS inhibition suggested that TNF-alpha was mediating apoptosis, but not necrosis, through the stimulation of NO production. The antiapoptotic activity of PGE1 was associated with a reduction of NO production, but was blocked by iNOS inhibition. This apparent contradiction was explained by the ability of PGE1 to enhance iNOS expression shortly after its administration and inhibit it later during d-GalN treatment. Anti-TNF-alpha antibodies did not reduce the exacerbation of d-GalN-associated cell death in hepatocytes by cocultured Kupffer cells.

Conclusion: TNF-alpha mediates D-GalN-induced apoptosis via NO production in cultured hepatocytes. The protective effect of PGE1 against D-GalN-induced apoptosis is probably through the induction of low iNOS expression that was followed by a reduction of iNOS expression and NO production induced by the hepatotoxin. The exacerbation of hepatocyte cell death by Kupffer cells was not related to TNF-alpha and NO.
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http://dx.doi.org/10.1155/2002/986305DOI Listing
November 2002

Influence of marginal donors on liver preservation injury.

Transplantation 2002 Aug;74(4):522-6

Unit of Liver Transplantation, Department of Surgery, Hospital Reina Sofía, Avenida Menéndez Pidal s/n, 14004-Córdoba, Spain.

Purpose: The purpose of this study was to assess the accumulated effects of marginal donor quality factors on liver preservation injury (LPI).

Methods: The most recent 400 consecutive liver transplantations at our institution were reviewed. Marginal liver donor criteria included the following: older than 60 years, an intensive care unit stay under ventilatory support for more than 4 days, a cold ischemia time more than 14 hr, high inotropic drug use, prolonged hypotensive episodes for more than 1 hr and less than 60 mm Hg, a peak serum sodium more than 155 mEq/L, and high levels of bilirubin, alanine transferase, or amino transferase. The type of steatosis (macrovesicular or microvesicular) was quantified in four categories: no steatosis, mild (<30%), moderate (30-60%), and severe (> 60%). LPI was stratified histologically in four levels: no damage, mild, moderate, and severe injury. These variables were included in a logistic regression analysis for prediction of the probability of the appearance of LPI.

Results: Five variables showed an independent influence on LPI: high inotropic drug use (odds ratio [OR]=1.56), donor age (OR=1.017 per year), moderate to severe macrovesicular steatosis (OR=3.63), cold ischemia time (OR=1,109 per hour), and prolonged stay in an intensive care unit (OR=1.79). Severe LPI was present in 32.7% of the grafts from donors without any factor of the model; in 46.8% from donors with one factor (P =0.09); in 66.2% from donors with two factors (P =0.006); and in 78.3% from donors with at last three factors (P =0.002) (global P=0.0001; chi2 =21.8).

Conclusions: LPI can be potentially predicted based on donor and graft conditions. Accumulation of factors is correlated with an increased effect on LPI.
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http://dx.doi.org/10.1097/00007890-200208270-00015DOI Listing
August 2002